Novel Method

ABSTRACT

The present invention is directed to a novel method for reducing intrapatient variability in pharmaceutically active agent which is suitably not absorbed in the stomach, such as paracetamol, containing formulations in patients having gastric dysmotility, or a method of improving analgesia in a diabetic patient, or improving absorption of an active agent is a patient with gastric dysmotility, which methods comprises administering orally to said patient in need thereof a pharmaceutical dosage form comprising a first active agent, calcium carbonate, at least one first binding agent, and at least one disintegrating agent as intragranular components in the form of a granulate, and as an extragranular component at least one hydrophilic colloid, an optionally a second binding agent, calcium carbonate, a super disintegrant, and a second active agent.

FIELD OF THE INVENTION

The present invention is directed to novel methods of use forparacetamol containing formulations which deliver rapid dissolution ofthe active agent followed by improved absorption in patients withdelayed gastric emptying.

BACKGROUND OF THE INVENTION

The present invention is the use of a paracetamol formulation that hasunexpectantly been shown to have improved pharmacokinetic profiles inpatients having gastric dysmotility or gastroparesis. Historically,diabetes has been shown to reduce gastric motility (gastroparesis) by upto 50% in patients as compared to non-diabetic individuals.

Involvement of the autonomic nervous system in patient having diabetesmellitus includes gastric enteropathy characterized by gastrointestinaldysmotility. Bassotti, G., Recenti Prog Med. 82: 334-337 (1991).Long-standing diabetes mellitus may reduce gastric emptying in up to 50%of patients. O'Mahony et al., Drugs Aging, 19: 515-527 (2002). Theimpact of various age-related diseases on gastrointestinal motility inthe elderly can also include those patients with depression whichsignificantly prolongs whole-gut transit time; hypothyroidism, chronicrenal failure, and idiopathic Parkinson's disease. Frequently drugs inthe elderly can cause disordered gastrointestinal motility, such asanticholinergics, opioid analgesics and calcium antagonists.

The importance of dysmotility in patients, particularly the elderly, mayresult in serious clinical consequences where clinical response to amedication is delayed, such as in delayed levodopa absorption or withdiuretics. As opioids and anticholinergics already have inhibitoryeffects on gastric emptying, this may delay the absorption of otherdrugs. Consequently, the need for consistent, low intrapatientvariability on absorption of drugs, such as analgesics, in such apatient population is very much in need.

SUMMARY OF THE INVENTION

The present invention is directed to a novel method for reducingintrapatient variability in pharmaceutically active agent which issuitably not absorbed in the stomach, such as paracetamol containingformulations in patients having gastric dysmotility, and the presentinvention is directed to a method for improving analgesia in a diabeticpatient, or for improving absorption of an active agent is a patientwith gastric dysmotility, which methods all comprises administeringorally to a patient in need thereof, a pharmaceutical dosage formcomprising a first active agent, suitably paracetamol, calciumcarbonate, at least one first binding agent, and at least onedisintegrating agent as intragranular components in the form of agranulate, and as an extragranular component at least one hydrophiliccolloid, an optionally a second binding agent, calcium carbonate, asuper disintegrant, and a second active agent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel method of improving thevariability of absorption of an active agent between patients who havegastric dysmotility. Gastric dysmotility is also known as gastrichypomotility. Gastric hypomotility, in otherwise normal patients, can beinduced by a variety of environmental, pharmacological and physiologicalfactors. Importantly, delayed gastric emptying can have a deleteriouseffect on the absorption of drugs such as paracetamol, which areabsorbed primarily in the small intestine. This can result in delayedand inconsistent plasma levels of a medicine, and can cause discomfortwhen the particular medicine is a pain medicine such as paracetamol.

For purposes herein the active agent is suitably not one which isabsorbed in the stomach. The present formulation is intended tointroduce the active agent into the duodenum at an increased rate overan otherwise standard formulation of the active agent. Therefore, anyactive that is absorbed primarily after the pyloric sphincter (e.g., atthe bottom of the stomach) rather than in the stomach itself is expectedto show a more rapid, and a more consistent pharmacokinetic profile. Aswill be described herein in greater detail, the active agent,paracetamol has been chosen herein to describe the invention.Paracetamol in a standard dosage form has been shown to not contributeto the emptying rate of the drug from the stomach.

Paracetamol is an analgesic and antipyretic drug effective in relievingmild to moderate pain. The recommended therapeutic dose in the UnitedKingdom is 500-1000 milligrams (mg) every 4 to 6 hours (hr) up to amaximum of 4000 mg daily. The absolute oral bioavailability is about 80%and is independent of dose in the range of 5-20 mg/kg. Peak plasmalevels are achieved between 0.5 and 3 hour post-dose depending on theformulation.

Paracetamol has a mean plasma half-life of 2.4 hours in adults with arange of 1.5-3.0 hours. It varies relatively little between individuals,and is not prolonged to a clinically significant extent at the extremesof age. It is not bound to plasma protein to any extent and the volumeof distribution is about 0.9 litre/kilogram (1/kg) body weight.

Oral paracetamol is primarily absorbed from the upper small intestineand for standard solid dose tablet formulations the rate of absorptionis limited by i) the process of tablet disintegration/dissolution andii) by gastric emptying from the stomach into the upper small intestine.

Diabetes mellitus (type 2) is the most common cause of impairedgastrointestinal motility in the elderly. Gastric emptying can beabnormal in this population and therefore impact on the absorptionprofile of the active agent, such as paracetamol. The present inventionhas investigated the absorption profile of paracetamol from a standarddosage form and from a granulate dosage form of paracetamol and calciumcarbonate, and has determined that the relative difference in absorptionprofiles observed in healthy volunteers is changed when using diabeticpatients as a model of gastric dysmotility.

One embodiment of the present invention is directed to the use of agranulate composition of paracetamol as will be further describedherein, that has now been shown to provide significantly greaterabsorption at 30 minutes, and to have statistically significant Cmaxplasma levels at 30 minutes over standard paracetamol containingformulations in patients have gastric dysmotility. In one embodiment ofthe invention, those patients having gastric dysmotility are diabeticpatients.

The present invention has also shown to provide significantly greaterabsorption at 60 minutes over standard paracetamol containingformulations in patient have gastric dysmotility.

While the present invention has also been shown to have a shorter timeto maximal concentration (Tmax) as compared to standard paracetamol,however, the difference was not statistically significant. Overall thediabetic population shows slower absorption of paracetamol from bothtreatments when compared with results observed in healthy volunteers andthis could be attributed in part to the gastric enteropathy that isknown to occur in diabetes mellitus. Therefore, patients with type 2diabetes are a suitable dysmotility model which can be used to evaluatethe PK profile of paracetamol from two different formulations.

The paracetamol containing dosage form comprises paracetamol, calciumcarbonate, at least one binding agent, and at least one disintegratingagent, as intragranular components in the form of a granulate, and as anextragranular component, a hydrophilic colloid, an optionally a bindingagent, calcium carbonate, a super disintegrant, and/or additionalparacetamol. A formula containing such excipients has been described inWO 2007/118063, filed 3 Apr. 2007 whose disclosure is incorporated byreference herein in its entirety.

While not wishing to be limited to such a dosage form, it is alsobelieved that the paracetamol containing dosage forms as described inRoberts et al., US 2007/0141144, published Jun. 21, 2007 or an earlierbut related WO publication, WO 2005/15344, published 8 Dec. 2005, whosedisclosures are incorporated by reference herein, are also acceptablefor use in the methods described herein.

A fast release composition according to this invention disintegrates anddissolves rapidly in the stomach so as to facilitate fast absorption ofthe active agent into the circulatory system. For purposes herein, “fastrelease” means wherein at least 60% of the active has dissolved from thecomposition at 180 seconds, as determined by the dissolution testingmethod described herein. In another embodiment, suitably at least 70%,of the active has dissolved. In another embodiment at least 80% hasdissolved, and in yet another embodiment at least 90% of the activeagent has dissolved from the composition at 180 seconds. A suitabledissolution testing method for this purpose utilizes the same conditionsas disclosed in WO 02/100391, namely a USP paddle apparatus rotating at30 rpm, employing 900 ml of 0.05M HCl at 37° C. as the dissolutionmedium. In this reference, the percentage of paracetamol dissolved wasdetermined at fifteen minutes, rather than the 180 seconds as describedin US 2007/0141144. Also noted as suitable are the dissolution methodsdescribed at 5, 10, 15, 20, 25 and 30 minutes in Rostami-Hodjegan etal., Drug Development and Industrial Pharmacy, 28(5), pp 533-5439(2002).

While paracetamol release rates have been determined for a number ofcommercially available paracetamol products and found to range fromabout 12% to about 32%, a fast release of the active is only part of thepresent invention. Not only must the active be released from its dosageform, the active must also be emptied from the stomach into the duodenumat a rate which is consistent from patient to patient, and in particularin patients with decreased gastric motility be emptied as near normal aspossible.

Accordingly one aspect of the invention provides for a pharmaceuticalcomposition comprising an active, calcium carbonate, at least onebinding agent, and at least one disintegrating agent, as intragranularcomponents in the form of a granulate.

The granulate may optionally be combined with one or more suitableextragranular components, and may be in the form of a “tablet” which mayincludes tablet of any shape, and includes caplets, which are tabletshaving a capsule shape. The formulation may be placed into capsules, orbe available in unit dose sachets.

When in a unit dosage form, a composition according to the inventioncomprises a therapeutically effective amount of the active. In oneembodiment the active is paracetamol, by which is meant an amount ofparacetamol sufficient to achieve a therapeutic benefit. Suitably suchan amount is in the range 250 mg to 1000 mg per unit dosage form (e.g.per tablet) and typically is either 325 mg or 500 mg.

While the active is present as an intragranular component, it isrecognized that a limited amount of the same or a different active, mayalso be present extragranularly. Although it has not been prepared andtested, another embodiment of the invention includes a formulationwherein the active agent is solely dispersed in the formulation asextragranular component.

A pharmaceutical composition according to the invention comprisesintragranular calcium carbonate. Suitably the calcium carbonate contentin the granulate does not exceed 20.0% by weight of the composition, andfor example in one embodiment is present in an amount of about 5.0% toabout 20.0% by weight, suitably from about 5.0% to about 15.0% by weightof the composition. In an alternative embodiment the calcium carbonatecontent is from about 8.0% to about 15.0% by weight of the composition.

In one embodiment according to the invention the paracetamol content inthe granulate is in the range 70.0 to 80.0% by weight of the compositionand the calcium carbonate in the granulate is in the range 8.0% to 15.0%by weight of the composition. For example a 500 mg paracetamolcomposition may comprise 30 mg to 110 mg intragranular calciumcarbonate, and a 325 mg paracetamol composition may compriseintragranular 20 mg to 72 mg calcium carbonate.

While calcium carbonate is present as an intragranular component, it isrecognized that a limited amount of calcium carbonate e.g. up to aboutan additional 25.0% by weight of the intragranular calcium carbonatecontent of the composition, may also be present extragranularly. In oneembodiment a composition according to the invention comprises, as anextragranular component, calcium carbonate in an amount ranging fromabout 0.1% to about 10.0% by weight of the intragranular calciumcarbonate amount therein.

A composition according to the invention comprises intragranularly, acomponent that functions as a binder, such as one or more bindingagents. Suitably the binding agent may comprise a first binding agentand a second binding agent. Suitable binding agents for use hereininclude conventional binding agents used in the art such as starches,polymers and cellulose derivatives or combinations thereof.

If the binding agent includes a starch, suitably it is of vegetableorigin such as corn (or maize) starch, modified corn starch, wheatstarch, modified wheat starch, potato starch, or pregelatinized starche.g. available commercially as Starch 1500 G or Prejel; or a combinationof two or more thereof.

Combinations of starch with other binding agents, such as thosedescribed herein, are also envisaged within the scope of the invention.In one embodiment, suitably the starch is pregelatinized starch, whereit is the sole or a first binding agent. Pregelatinized starch is astarch that has been chemically and/or mechanically processed. Typicallypregelatinized starch contains 5% of free amylase, 15% of freeamylopectin, and 80% unmodified starch. Pregelatinized starch may beobtained from corn (or maize), potato or rice starch. It has been foundthat paracetamol dissolution rate is adversely affected in a compositioncomprising as intragranular components: paracetamol, calcium carbonate,maize starch, pregelatinized starch, Povidone K25, and potassiumsorbate, wherein the weight ratio of pregelatinized starch to maizestarch is about 2.3:1. Accordingly if the binding agent comprises amixture of corn (or maize) starch and pregelatinized starch, then theweight ratio of pregelatinized starch to corn (or maize) starch is atleast 3.0:1.0. In one embodiment of this invention, the weight ratio ofpregelatinized starch to corn (or maize) starch is at least 5.0:1.0.

Suitably, when present in a composition of the invention, the starch ispresent in the granulate in an amount from about 1.0% to about 30.0% byweight of the composition, typically from about 5.0% to about 20.0% forexample from about 8.0% to about 15.0% by weight of the composition.

If the binding agent includes a polymer, suitably it is polyvinylpyrrolidone or povidone (PVP), polyvinyl alcohol (PVA), polyethyleneoxide, polaxamer, polymethacrylate e.g. a carbomer, polyethylene glycol(PEG) such as PEG 3350 and calcium polycarbophil; or a combination oftwo or more thereof. Combinations of a polymer with other bindingagents, such as those described herein, are also envisaged within thescope of the invention. When the polymer comprises PVP, it will suitablycomprise a molecular weight of about 30,000 e.g. available commerciallyas PVP K25. Suitably, when present in a composition of the invention,the polymer is present in the granulate in an amount from about 1.0% toabout 10.0% by weight of the composition, typically from about 1.5% toabout 5.0% by weight of the composition.

In one embodiment, a polymer such as PVP is present as a second bindingagent. In one embodiment a starch such as pregelatinized starch ispresent as a first binding agent, in an amount ranging from about 10.0%to about 15.0% by weight of the composition, and a polymer such as PVPis present as a second binding agent in an amount ranging from about1.5% to about 5.0% by weight of the composition. Suitably such anembodiment is substantially free of corn (or maize) starch, for examplecomprising no more than an amount ranging from about 0.0% to about 1.0%of corn (or maize) starch.

If the binding agent includes a cellulosic derivative, suitably itincludes at least one of hydroxypropyl cellulose (HPC) (low to mediumviscosity versions thereof) e.g. as may be available commercially underthe brand name Klucel® from the Aqualon division of Hercules Inc., DowChemical Company e.g. Klucel GF, Klucel JF, Klucel LF and Klucel EF;hydroxypropylmethyl cellulose (HPMC) (low to medium viscosity versionsthereof) e.g. as may be available commercially under the brand nameMethocel® from the Dow Chemical Company e.g. Methocel E15Premium,Methocel E3Premium LV, Methocel K100LV; microcrystalline cellulose(MCC), carboxymethylcellulose (MC), sodium carboxymethylethyl cellulose;or a combination of two or more thereof. Combinations of a cellulosicderivative with other binding agents noted above are also envisagedwithin the scope of the invention.

The term “low to medium” viscosity as used herein means a viscosity inthe range of from about 15 to about 1000 mPa·s. It is recognized in theart that the determination of the viscosity of cellulosic derivatives isbased upon standard techniques and grading in the art e.g. for HPMC,viscosity may be determined at 20° C. with a 2% solution using aUbbelohde viscometer, or for HPC, viscosity may be determined at 25° C.with a 2-10% solution using a Brookfield LVF viscometer. Generally thecellulosic derivative is present in the granulate in an amount rangingfrom about 0.5% to about 5.0% by weight of the composition. It isrecognized in the art that certain cellulosic derivatives, such as HPMC,will have varying roles in a formulation, depending upon the amountused. For example HPMC (low or medium viscosity) may function as abinding agent, a coating agent, or as a matrix forming agent. It hasbeen found that when HPMC (low or medium viscosity) is used at about10.0% by weight of the composition, the dissolution rate of paracetamolis slowed down, probably owing to the extended-release properties ofHPMC. According to the present invention, when used as a binding agent,the HPMC is present in an amount typically not more than 2.5% by weightof the composition, for example in an amount from about 1.0% to about2.5% by weight of the composition.

The total amount of binding agent present intragranularly in acomposition according to the invention is suitably in an amount rangingfrom about 1.0% to about 30.0% by weight of the composition, for examplefrom about 2.0% to about 25.0% by weight of the composition, oralternatively from about 5.0% to about 20.0% by weight of thecomposition.

While a binding agent is present as an intragranular component, it isrecognized that a modest amount of binding agent e.g. up to about anadditional 5.0%-10.0% by weight of the intragranular binding agentcontent of the composition, may also be present extragranularly. In oneembodiment a composition according to the invention comprises, as anextragranular component, a binding agent in an amount ranging from about0.1% to about 10.0% by weight of the intragranular binding agent amounttherein.

A composition according to the invention comprises, as an intragranularcomponent, at least one component one that functions as a disintegrant,and may include at least two disintegrating agents. Suitabledisintegrating agents include a non-super disintegrant, a superdisintegrant or a combination of both. Suitable non-super disintegrantsinclude conventional disintegrants such as starch (corn or maize),pregelatinized starch, e.g. Starch 1500 G, clays (Veegum or Bentonite),microcrystalline cellulose, cellulose or powdered cellulose. It isrecognized in the art, that some excipients may perform more than onerole in a given pharmaceutical formulation. For example certainexcipients, e.g. starches including pregelatinized starch, andmicrocrystalline cellulose (hereinbefore identified as binding agents)function as both binders and disintegrants. Accordingly it will beunderstood that the same excipient may act as both a binding agent and adisintegrating agent. In such cases, inclusion of a disintegrating agentin addition to a binding agent is entirely optional. Equally, in suchcases, inclusion of a binding agent in addition to a disintegratingagent is entirely optional.

One embodiment of the invention provides for as intragranularcomponents, paracetamol and calcium carbonate, and at least one bindingagent which is microcrystalline cellulose or starch, wherein the starchis corn (or maize) starch, modified corn starch, wheat starch, modifiedwheat starch, potato starch, pregelatinized starch or a combination oftwo or more starches thereof, with the proviso that if the binding agentcomprises a mixture of corn (or maize) starch and pregelatinized starchthen the weight ratio of pregelatinized starch to corn (or maize) starchis greater than from about 3.0 to 1.0; and optionally a disintegratingagent; and one or more pharmaceutically acceptable ingredients asextragranular components.

The compositions herein may include a non-super disintegrant which maybe present intragranularly, extragranularly or both intragranularly andextragranularly. When a non-super disintegrant is either absent from thecomposition or is present only extragranularly, the disintegrating agentwill suitably comprise a super disintegrant, present intragranularly.

Suitably a non-super disintegrant will be present intragranularly in anamount ranging from about 5.0% to about 30.0% by weight of thecomposition, suitably from about 5.0% to about 20.0% by weight of thecomposition. When present extragranularly, the non-super disintegratingagent, may also be present in an amount for example up to about anadditional 5.0% -10.0% by weight of the intragranular non-superdisintegrating agent content of the composition.

A super disintegrant, if used, may be present intragranularly,extragranularly or both intragranularly and extragranularly. It isrecognized that when a super disintegrant is either absent from thecomposition or is present only extragranularly, the disintegrating agentwill comprise a non-super disintegrant, present intragranularly. A superdisintegrant may be used intragranularly or extragranularly, in anamount ranging from about 0.5% to about 5.0% by weight of thecomposition. The total amount of super disintegrant may be in an amountranging from about 0.5% to about 10.0% by weight of the composition.

“Super disintegrants” represent a class of disintegrating agent whichmay generally be used in lower amounts in pharmaceutical preparations,as compared to conventional disintegrants. Examples of superdisintegrants include sodium starch glycolate, the sodium salt ofcarboxymethyl starch, modified cellulose and cross-linked polyvinylpyrrolidone. Sodium starch glycolate is available commercially under thetrade names Explotab® (Edward Mendell Co.), Primojel® (Generichem Corp)and Tablo® (Blanver, Brazil). An example of modified cellulose includescroscarmellose, the sodium salt of carboxymethyl cellulose.Croscarmellose is available commercially under the trade names AcDiSol®(FMC Corp.), Nymcel ZSX® (Nyma, Netherlands), Primellose® (Avebe,Netherlands), Solutab® (Blanver, Brazil). An example of a cross-linkedpolyvinyl pyrrolidone includes crospovidone, and is commerciallyavailable under the trade names Kollidon CL® or Kollidon CL-M (BasfCorp.), and Polyplasdone XL® (ISP Corp). Suitably the disintegratingagent comprises cross-linked polyvinyl pyrrolidone.

A composition according to the invention may optionally contain furtheradditional pharmaceutically acceptable extragranular components. Forexample a composition according to the invention may comprise ahydrophilic colloid such as alginic acid, carageenan, gellan, pectinand/or agar, as an extragranular component. Suitably the hydrophiliccolloid is alginic acid. When present, a hydrophilic colloid is presentin an amount ranging from about 1.0% to about 5.0% by weight of thecomposition.

In one aspect a composition according to the invention comprises alginicacid as an extragranular component.

Other pharmaceutically acceptable extragranular components include, butare not limited to, an antimicrobial agent e.g. potassium sorbate or aparaben i.e. one or more hydroxy benzoic acid esters e.g. methyl, ethyl.propyl or butyl, suitably singularly or as mixtures. In one embodimentof the invention a paraben is used.

In one embodiment the composition comprises paracetamol, calciumcarbonate, pregelatinized starch, and povidone as intragranularcomponents, and as extragranular components alginic acid andcrospovidone, and optionally other extragranular components, preferablycompressed into a tablet. Suitably, the alginic acid is present in anamount ranging from about 1.0% to about 5.0% by weight of thecomposition.

Additional pharmaceutically acceptable extragranular components includea dye; colorant; flavorant; compression aid; preservative; wettingagent; bulking agent; adhesive; sweetening agent; lubricant such asmagnesium stearate, calcium stearate, sodium stearate, stearic acid ortalc; and a flow aid or glidant such as colloidal silicon dioxide(Cab-O-Sil, Syloid™). Suitably, when present, a lubricant or flow aidare each used in an amount ranging from 0.1% to 5.0% by weight of thecomposition. It is recognized that additional pharmaceuticallyacceptable components may be present as intragranular components as wellas extragranular components.

In addition to paracetamol, compositions of the invention may alsocontain other pharmaceutically active agents for example otheranalgesics such as codeine, hydrocodone, oxycodone, tramadol andpropoxyphene; anti-inflammatory analgesics such as NSAIDs e.g. aspirinand ibuprofen; decongestants such as pseudoephedrine and phenylephrine;antitussives such as pholcodine and dextromethorphan; expectorants suchas guaifenesin and bromhexine; diuretics such as pamabrom; non-sedatingand sedating antihistamines such as diphenydramine, doxylamine andmepyramine; gastrointestinal agents such as metoclopramide; triptanssuch as sumatriptan; and muscle relaxants such as methocarbamol; andadjuvants, for example caffeine. As previously noted, pharmaceuticallyactive agents and adjuvants may be present intragranularly,extragranularly or both intragranularly and extragranularly.

In another aspect there is provided a composition comprising caffeineintragranularly, extragranularly or both intragranularly andextragranularly. Suitably the caffeine is present extragranularly. Inone embodiment the caffeine is in addition to an intragranularparacetamol containing formulation.

As used herein the term “pharmaceutically active agent” includes, but isnot limited to, drugs, dietary supplements, vitamins, minerals,nutraceuticals, and veterinary agents. This term includes bioactiveagents, active agents, therapeutic agents, or drug(s) as defined herein,and follows the guidelines from the European Union Guide to GoodManufacturing Practice. Such substances are intended to furnishpharmacological activity or other direct effect in the cure, mitigation,treatment, or prevention of disease or to affect the structure andfunction of the body. The pharmacological activity may be prophylactic,or for treatment of a disease state.

Drug substances include those intended for oral administration. Adescription of these classes of drugs and a listing of species withineach class can be found in Martindale, The Extra Pharmacopoeia,Twenty-ninth Edition, The Pharmaceutical Press, London, 1989. The drugsubstances are commercially available and/or can be prepared bytechniques known in the art.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

Example 1 Pharmacokinetic Profile in Gastric Dysmotility Patients

Long standing diabetes may have reduced gastric motility by up to 50%.Therefore, patients with type 2 diabetes were chosen as a dysmotilitymodel to evaluate the PK profile of paracetamol from two differentformulations. This study was a single centre, two way, open label,randomized, single dose, cross over PK study. Subjects received a single1 gm oral dose of a formulation of the invention or standard paracetamolformulation, 2 hours after a standard meal, with randomly assignedpatients having a 24 hour wash out between dosing. 21 patients completedthe protocol, 18 males, and 3 females. Blood samples were taken 4 hourspost-dose for pharmacokinetic analyses.

The primary study objective was to compare early exposure, as assessedby rate of absorption (area under the curve [AUC]_(0-30 mins)). Otherearly exposure variables included time to maximum concentration(T_(max)), and inter-patient variability (coefficient of variation (CV))in AUC_(0-30 mins), AUC_(0-60 mins) and plasma concentration(C_(plasma)) at 30 minutes.

Standard Panadol tablets are film coated tablets containing 500 mgparacetamol, and contain as excipients, pregelatinized starch, maizestarch, talc, stearic acid, povidone, potassium sorbate, hypromellose,and glycerol triacetate.

The calcium carbonate/paracetamol formulation used herein contains 500mg paracetamol and is similar to that described in Example 6 of WO2007/118063.

Results

Paracetamol/Calcium Carbonate Formula Panadol Standard p-Value p-Value(n = 21) (n = 21) Median (Wilcoxon (CV Square Parameter mean, median, CV% mean, median, CV % difference test) Rank test) AUC0-30 min 0.45, 0.28,153.1 0.14, 0.04, 215.8 0.18 0.0004 0.0522 (ug/ml · h) AUC0-60 min 2.10,1.38, 102.8 0.84, 0.26, 174.9 1.02 0.0014 0.0801 (ug/ml · h) Cplasma at2.48, 1.52, 125.0 0.84, 0.19, 282.7 1.08 0.0002 0.0693 30 mins (ug/ml)Tmax (h) 2.36, 2.50, 41.4 2.77, 2.75, 33.5 −0.25 0.1448 — Cmax (ug/ml)8.99, 7.97, 34.9 9.49, 9.77, 28.9 — — — AUC0-t min 21.01, 18.92, 35.118.5, 16.04, 7.9 — — — (ug/ml · h)

AUC₀₋₃₀ min (primary objective) was statistically significantly greaterfor the Paracetamol/calcium carbonate containing formulation than forstandard paracetamol (p=0.0004).

AUC₀₋₆₀ min and Cplasma at 30 minutes were statistically significantlygreater (p=0.0014) and higher (p=0.0002), respectively, forParacetamol/calcium carbonate containing formulation compared tostandard paracetamol.

The time to maximum concentration (Tmax) was shorter forParacetamol/calcium carbonate containing formulation compared tostandard paracetamol but the difference was not statisticallysignificant (p=0.1448).

There was a trend towards statistical significance for the comparison ofCVs for AUC₀₋₃₀ min (p=0.0522), AUC₀₋₆₀ min (p=0.0801) and Cplasma at 30minutes (p=0.0693) in favour of Paracetamol/calcium carbonate containingformulation.

The Paracetamol/calcium carbonate containing formulation was absorbedmore rapidly than standard paracetamol tablets, and demonstrated a trendtowards less inter-patient variability (based on the coefficient ofvariation) in this population of diabetic patients.

The planned sample size was less than desired, and may explain why therewas a lack of statistical significance for the Tmax comparison obtained.Overall the tested population (diabetics) in this study showed slowerabsorption of paracetamol from both treatments when compared withresults observed in healthy volunteers and this could be attributed inpart to the gastric enteropathy that is known to occur in diabetesmellitus. However, the paracetamol/calcium carbonate containingformulation appears to maintain the advantages of fast and consistentabsorption shown in previously healthy volunteers, even in thosepatients with diabetes mellitus.

Example 2 Pharmacokinetic Parameter Study

It had previously been determined in a clinical study that theParacetamol/calcium carbonate containing formulation (as describedabove) is emptied from the stomach more rapidly than a standardparacetamol (SP) tablet formulation. The study below compares the PKparameters of Paracetamol/calcium carbonate containing formulation andthe standard paracetamol tablet, and to assesses their variability,since these can influence analgesic efficacy and response rates.

Methods

A total of 76 healthy volunteers were recruited in an open-label,randomised, 8-way crossover study. Each formulation was administered ina replicate fashion, with a single 1 g dose taken 2 hours after astandard meal on 4 separate days. Blood samples were taken up to 10hours after the initial dose and 4 hours after the replicate doses forpharmacokinetic (PK) analysis.

The primary objectives were: early exposure (rate of absorption,AUC_(0-30 mins), after both initial and replicate dosing) , inter(between)-subject variation (inter-CV %, after initial dose) andintra-subject variation (intra-CV %, after replicate dosing). Secondaryobjectives included AUC_(0-60 mins), plasma concentration at 30 mins(C_(p1 30 mins)) and percentage drug absorbed (PDA) at 30 and 60 minutes(measured by deconvolution analysis, variance measured for initial doseonly).

Results

AUC_(0-30 mins) for both the initial dose and after replicate dosingwere very significantly higher for the Paracetamol/calcium carbonatecontaining formulation versus standard paracetamol formulation (initialdose: 0.98 versus 0.10 μg·h/ml [median difference 0.77, 95% CI0.53-1.01, p<0.0001]; replicate dosing: 1.23 versus 0.15 μg·h/ml [mediandifference 0.99, 95% CI 0.81-1.19, p<0.0001]).

Inter-CV % for this parameter was significantly lower for theParacetamol/calcium carbonate containing formulation versus standardparacetamol formulation (84.4% versus 192%, p<0.0001).

Similarly, there was a significant difference for intra-CV % forAUC_(0-30 mins) (60.6% versus 116%, p<0.0001). Similar reductions ininter-CV % and intra-CV % were observed for AUC_(0-60 mins) andC_(p1 30 mins) along with inter-CV % for PDA_(30 mins) andPDS_(60 mins).

Conclusions

These data clearly show that paracetamol absorption with theParacetamol/calcium carbonate containing formulation is significantlyfaster than absorption with standard paracetamol formulation tablets.Importantly, paracetamol absorption with the Paracetamol/calciumcarbonate containing formulation also shows significantly less inter-and intra-subject variability. Taken together, these data have clearclinical implications in terms of a patient population obtaining rapid,and consistent, pain relief with this valuable first-line pain therapyand therefore avoiding potential side effect issues with second-linetreatments such as the NSAIDs.

Example 3 Disintegration and Gastric Emptying

Tablet disintegration and dissolution are key factors in in vivo speedof absorption and downstream pharmacokinetic parameters. Using theParacetamol/calcium carbonate containing formulation an in vivo gammascintigraphy investigation of tablet disintegration and gastric emptying(GE) was conducted.

Methods

This single-dose, cross-over study involved 24 healthy volunteers. Allparticipants ate a standard radio-labelled breakfast 2 hours (h) beforetaking the study medication (1 g paracetamol as either asParacetamol/calcium carbonate containing formulation (described above)or a standard paracetamol tablet formulation described above (SP)[¹¹¹indium-DTPA-labelled tablet]).

The rate of disintegration was measured using gamma scintigraphy afterdefining the stomach area as the region of interest. Data were analysedusing the WebLink® image analysis program. Onset and completion oftablet disintegration were determined by qualitative assessment ofscintigraphic images. Tablet gastric emptying was determined byquantifying the amount of activity remaining in the stomach at a seriesof time points. Two parameters were used to assess GE: time to 50%emptying (T₅₀) and time to 90% emptying (T₉₀). Onset of GE wasdetermined by qualitative assessment of scintigraphic images.

Results

Both time to onset and completion of disintegration were significantlyfaster for the Paracetamol/calcium carbonate containing formulation thanfor the standard paracetmol formulation (6.4±4.3 versus 46.7±20.5 min,p<0.0001 and 12.9±26.4 versus 69.6±30.2 min, p<0.0001). Similarly, forGE, time to onset (41.9±28.8 versus 85.0±28.2, p<0.0001), T₅₀ (72.4±36.4versus 100.7±30.6, p=0.0013) and T₉₀ (128.4±41.2 versus 142±33.8,p=0.10) were shorter for the Paracetamol/calcium carbonate containingformulation than for the standard paracetmol formulation. The time forGE of the standard meal did not differ between the Paracetamol/calciumcarbonate containing formulation or the standard paracetmol formulation.Furthermore, while 75% of subjects taking the Paracetamol/calciumcarbonate containing formulation showed onset ofdisintegration/dissolution within 5 mins, none of the standard groupexhibited onset at this time point.

Conclusions

The Paracetamol/calcium carbonate containing formulation had a highlysignificant in vivo tablet disintegration advantage over the standardparacetamol formulation in this scintigraphy study. This correlates withenhanced GE for paracetamol with the Paracetamol/calcium carbonatecontaining formulation compared with standard paracetamol formulations.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A method for improving analgesia in a diabeticcomprising administering to said patient in need thereof an orallyadministered pharmaceutical dosage comprising a first active agent whichis paracetamol present in an amount of about 60 to about 80% by weight,calcium carbonate present in an amount of about 5 to about 20% byweight, at least one first binding agent, and at least onedisintegrating agent as intragranular components in the form of agranulate, and as an extragranular component at least one hydrophiliccolloid.
 2. A method for improving absorption of paracetamol in apatient with gastric dysmotility comprising administering to saidpatient in need thereof an orally administered pharmaceutical dosagecomprising a first active agent which is paracetamol present in anamount of about 60 to about 80% by weight, calcium carbonate present inan amount of about 5 to about 20% by weight, at least one first bindingagent, and at least one disintegrating agent as intragranular componentsin the form of a granulate, and as an extragranular component at leastone hydrophilic colloid, an optionally a second binding agent, calciumcarbonate, super disintegrant, and a second active agent.
 3. A methodfor improving analgesia in a diabetic comprising administering to saidpatient in need thereof an orally administered pharmaceutical dosagecomprising a) paracetamol; b) at least one agent which contributes todissolution selected from sodium carbonate, ammonium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium carbonate, magnesiumcarbonate, disodium glycine carbonate, sodium glycine carbonate, lysinecarbonate, arginine carbonate, or combinations of two or more of theabove; c) at least one water uptake agent selected from cross-linkedpolyvinylpyrrolidone (crospovidone), croscarmellose sodium, sodiumstarch glycolate, povidone, starch, starch derivatives, low substitutedhydroxypropylcellulose, hydroxypropylcellulose, alginic acid, sodiumalginate, calcium sulfate, calcium carboxymethylcellulose,microcrystalline cellulose, powdered cellulose, colloidal silicondioxide, docusate sodium, guar gum, magnesium aluminum silicate,methylcellulose, polacrilin potassium, silicified microcrystallinecellulose, magnesium oxide, tragacanth, mannitol, sorbitol, xylitol,sucrose, lactose, fructose, maltose, polyethylene glycol, amino acids,cyclodextrin, urea and/or polyvinylpyrrolidone; and wherein at least 70of the paracetamol is dissolved from the formulation within 180 secondsin USP dissolution apparatus 2 with 900 ml of 0.05 N hydrochloric acidat 30 rpm and 37° C.